Good afternoon, everyone, and welcome to the Arrowhead Pharmaceuticals Virtual R&D webinar. At this time, all attendees are in a listen-only mode, and a question -and -answer session will follow the formal presentations. If you would like to submit a question, please use the Q&A text box underneath the webcast player to ask a question. As a reminder, this call is being recorded, and a replay will be made available on the Arrowhead website following the conclusion of the event. I would now like to turn the call over to Vince Anzalone, Senior Vice President of Finance and Investor Relations at Arrowhead Pharmaceuticals. Please go ahead, Vince.
Thank you, Tara, and thanks, everybody, for joining us today to discuss the ARO-MAPT interim results from the phase I/II study and the first results with our new TRiM delivery system for CNS. Really excited about these data. Just before we start, I just want to make sure everybody knows we will be making forward-looking statements today, so refer to all the risk factors in our SEC filings. Here is the flow of the day. I am going to give a quick introduction. Our CEO, Chris Anzalone, will talk about how this ushers in a new era for RNAi therapeutics in the brain. Dr. Adam Boxer from UCSF will talk about the role of tau in Alzheimer's disease and other primary tauopathies.
James Hamilton, Arrowhead's Head of R&D and Chief Medical Officer, will talk about the development of the new TRiM CNS subQ delivery platform on how it applies to ARO-MAPT and some of our initial preclinical results with the platform, as well as with ARO-MAPT. Then he will move on to the interim clinical results from the phase I/II study. Then Chris will come back and talk about some key takeaways, and then we will have time for a handful of questions from the panel after that. Before we start, I just want to introduce Dr. Boxer. He is a Professor of Neurology at UCSF. He is the endowed professor in memory and aging, and importantly, he runs their clinical trials research unit for both Alzheimer's as well as frontotemporal dementia, which is one of those primary tauopathies that we will talk about. We are very fortunate to have him today.
Please, by all means, ask any questions you want because he knows all the answers. So thank you, Dr. Boxer, for joining us. Now I will turn the call over to Chris.
Thanks, Vince. Back in 2009, we decided to focus Arrowhead on RNAi. The field was in its infancy, but we believed that if we could develop the base technology and overcome delivery challenges, RNAi could be a truly revolutionary modality. We also believed that part of its power was in its potential breadth, so we sought to bring it to wherever disease is. As such, our early focus was to create a set of platforms capable of safely and efficiently bringing RNAi to different organ systems and cell types. Today is not the culmination of this drive. We are always building, always expanding, but it is a significant milestone, an important day. Next slide. Today, we present Arrowhead's first clinical proof of concept for ARO-MAPT and, importantly, our expanded TRiM platform for CNS delivery. There are several important points going into this early data release.
First, the term holy grail is overused, but I do believe that delivering oligonucleotides via subcutaneous administration to the brain is a therapeutic holy grail. Second, broad distribution within the brain is critical for treating many indications, and animal studies across rodent and non-human primate species suggest that our TRiM platform is capable of this. Third, a good durable and deep knockdown of at least 50%-60% was our goal, and the ability to detect this via the cerebral spinal fluid would be helpful. All of these were born out in animal studies. Fourth, we think the combination of employing RNAi in the brain with simple subcutaneous administration, potentially at home, that provide deep knockdown across brain regions lasting several months between injections, likely opens the possibility of treating many conditions from neurodegenerative to psychiatric to obesity. This feels like a company's worth set of potential value unto itself.
Next slide. Today's data have near-term importance beyond ARO-MAPT. As shown here, we currently have one wholly owned and one partnered candidate in the clinic using the TRiM CNS platform, and we expect to add another partnered candidate in the clinic in 2027. In addition, we plan to introduce at least three new wholly owned CNS candidates to the clinic over the next 12 months alone. I expect CNS candidates to be an increasingly important part of our pipeline in the near to midterm. But let's also be clear. Today is about ARO-MAPT and the important data we have generated thus far. We will show deep and durable knockdown in the CSF, and this is only after loading doses. We may see another step down in both knockdown and durability in the multiple dose cohorts as those data become available.
Given our animal data, we have a high degree of confidence that knockdown is occurring consistently across brain regions. As you will hear, there is substantial evidence that tau reduction may be important for treating Alzheimer's disease, and we think it is clearly important in primary tauopathies. Next slide. Dr. Boxer.
Good morning, everyone. Happy to present to you today and tell you a bit about the role of tau in Alzheimer's disease and other tauopathies. The objectives are to review the current treatment landscape in Alzheimer's disease, understand the implications of recent therapeutic advances in amyloid and tau therapies, evaluate the rationale for tau-targeting therapies. I want to frame some of the key consideration for the next generation therapies and talk about tau reduction for the treatment of primary tauopathies, which seems like a very exciting possibility.
Some people may be familiar with the history of research in Alzheimer's disease and other neurodegenerative diseases of aging. But in general, in the diseases that we call tauopathies, when we look at someone's brain after they've a protein-like tau, you can see that, for instance, in Alzheimer's disease, both the amount and the anatomical location of this insoluble protein, this dark brown stuff that you see, is strongly correlated with the severity of symptoms and the types of symptoms that the patient experienced during life. This is true not just for Alzheimer's disease, and again, in the upper left-hand corner, these are the famous Braak stages of Alzheimer's disease that we use neuropathologically to stage Alzheimer's disease, but they're also recapitulated now with tau-sensitive PET ligands.
It's also true in other tauopathies that we call primary tauopathies, like progressive supranuclear palsy, Richardson syndrome on the bottom left, and on the right, chronic traumatic encephalopathy, the disease that many football players and others who have had repetitive brain injuries get. It stands to reason that if the amount and the anatomical location of this insoluble tau is strongly correlated with the symptoms during life, then one treatment approach might be to try and either reduce this tau in the brain or prevent its buildup in the first place. What is tau? Tau was initially thought just to be a protein that binds to structures within neurons called microtubules, and that is an important role for tau, but over the past decade or two, we've learned that tau plays many important roles in neurons in the brain.
It is in the nucleus, and can bind to nucleic acids like DNA and RNA. It seems to also play a role in energy metabolism in neurons, in the structures called the mitochondria. Tau is also found in the synapse, the structures that allow one neuron to communicate with another, and it seems to play a role in the synaptic transmission or the communication that's mediated by neurotransmitter release from one cell or one neuron to another.
As I mentioned, the most common tauopathy, and the tauopathy that many of us are familiar with, is Alzheimer's disease, but we consider that to be a secondary tauopathy, and that is because although tau may be present in many people's brains due to normal aging, prior to the buildup of amyloid, we think that it's A-beta, or the plaques that are present in many people's brains, that really drive the overproduction and spread of tau throughout the brain. In primary tauopathies like progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and individuals with tau mutations, we think it's the tau itself that's really doing all the damage on its own, and we don't know, as far as what's maybe promoting its spread throughout the brain.
There's also quite a bit of evidence from genetic studies, like genome-wide association studies, that even though we often don't find insoluble tau at autopsy in the brains of patients with other diseases like Parkinson's disease, multisystem atrophy, or epilepsy, that from genetics, we know that tau is also very strongly linked to the risk and sometimes the progression of these diseases. We think that in all of these diseases, a central pathogenic mechanism is the accumulation of this toxic misfolded form of tau, and we call that toxic gain-of-function. There's quite a bit of evidence that this toxic misfolded brown stuff that I showed you on the previous slide may be spreading from one cell to the other throughout the brain. This causes neuronal and glial dysfunction, and eventually synaptic loss and degeneration.
As I'll mention in a moment, certain cells, including neurons, have evolved mechanisms to resist the spread and the buildup of this toxic gain-of-function. But we think in disease, this overwhelms the compensatory mechanisms. We think that also aging may be a part of this problem. In Alzheimer's disease, we have a big advantage in studying the progression of the disease. Many people may be familiar with these biomarker graphs. Some people call them Jack curves. Up in the top right-hand corner, you see a picture or a schematic of the tau protein. We know that the tau protein is usually cleaved into two pieces, and the N-terminal fragments are soluble and float around. What you can see is that in most people who go on to get clinical Alzheimer's disease, there's evidence from these biomarkers that we can measure in living humans.
We can measure soluble forms of A-beta or amyloid plaques using PET, that this soluble form of tau builds up in parallel with the amyloid plaques, which are often present for decades in individuals' brains before they develop symptoms of Alzheimer's disease. In Alzheimer's disease, we can also measure that insoluble tau that I showed you on the first slide using PET, and it's that second half on the right of the tau molecule that includes the microtubule binding region that seems to be accumulating. You can see there's sort of a point of inflection that occurs right before the onset of symptoms in most people who get Alzheimer's disease. We call that the catastrophe of Alzheimer's disease. Actually, it's Reisa Sperling and Keith Johnson who coined that term. But the important point is that patients can have amyloid plaques in their brains for decades without any symptoms.
But when that insoluble form of tau starts to accumulate and the catastrophe occurs, that's when people develop symptoms. The goal is to try and prevent the catastrophe, or at least to reduce it or blunt it. We know now that there are, and we clinicians are very excited that there are two FDA-approved anti-amyloid drugs that are commonly used now in the United States to treat Alzheimer's disease. These are data from the phase III trial of one of these drugs called donanemab. What you can see in the leftmost panel is that using a common global measure called the Clinical Dementia Rating scale sum of boxes, that treatment with donanemab in people who are already symptomatic with Alzheimer's disease, who have prodromal to mild disease, leads to a modest but significant reduction in the rate of decline by about 35%-40%.
And in parallel, you can see that the number of amyloid plaques is really profoundly reduced by the drug. So reducing amyloid is associated with this benefit in symptomatic Alzheimer's disease, but it's a relatively modest benefit, and it may not be enough. As I told you previously, there's been a longstanding hypothesis that it's really the tau that's the problem, and that it's the amyloid that's driving the tau and the catastrophe. So what we think is going on with anti-amyloid drugs is that you see in that dark red curve is that we can dramatically reduce the amount of amyloid plaques in the brain with either donanemab or lecanemab. But when we start, at least in patients who are very mildly symptomatic already, the catastrophe is already well underway in that dark blue line.
And what we know from tau PET is this has very modest effects on blunting or reducing the catastrophe. This leads to a modest effect on reduced cognitive decline. We think that a drug that could really effectively blunt the catastrophe, maybe by targeting tau itself, would have a much larger effect, and that's the hypothesis and that we're hoping to learn more about in future trials of tau therapies. Where did the idea of tau therapies come from? Well, people have been working on this for over 20 years. Some of the first experiments were done by Lennart Mucke and Erik Roberson at UCSF and the Gladstone Institute, and they showed that in Alzheimer's disease transgenic mice who carry a human Alzheimer's precursor protein transgene, that about 15% die after about six months.
But reducing the endogenous amount of tau by genetically knocking out one of the mouse tau alleles makes these mice resistant to human amyloid toxicity. Not only that, but in a different line of mice, reducing the tau even by just one allele or 50% makes them resistant to tonic-clonic seizures from a toxin called KA8. And so, again, this supports the idea that tau is important for maybe Alzheimer's disease, but also many other brain diseases. And so an effective tau drug might find a role in treating many neurological and neurodegenerative diseases. So fast-forward now over two decades, and we now know from Biogen's experience with diranersen. These are data from the phase I study.
This is an intrathecally administered tau antisense oligonucleotide that in patients with mild to moderate symptomatic Alzheimer's disease, that reduction of tau by up to about 60%, measured in the CSF using a CSF phosphorylated tau assay, is safe and well-tolerated. Remarkably, in these phase I results, we saw that for the first time, not only is it possible to stabilize the further accumulation or to maybe blunt that catastrophe, as measured by tau PET in a small number of people who were followed for two years. But there appeared to be less of that red stuff in the lower right-hand panel, which is the insoluble tau. Not only can a genetically targeted tau therapy seem to reduce the further accumulation of tau, it seems partially reversible. This was a really big deal for our field.
Many people were really excited because up until this point, we thought that accumulation of tau was an irreversible process. Now, we think that may not be true. I think as many people know, there's been a larger phase II trial of the same antisense oligonucleotide, diranersen. I'll show you the key results in just a moment. But the trial was overall negative, and we'll discuss why. But this drug has been announced to be moving to phase III, underscoring the promise of this approach for treating Alzheimer's disease. So, I want to just take a step back now and remind you a bit about the genetics and the biology of tau, because it's really important that you understand this for understanding the different diseases that we might wish to treat with a genetically targeted tau drug.
So this shows that tau is an alternatively spliced gene that gives rise to six protein isoforms in humans. They're named for the number of microtubule binding domains, either 3R, three microtubule binding repeat tau, or four microtubule binding repeat tau. In a normal adult brain or in someone with Alzheimer's disease, the ratio of these protein isoforms is equal. But in the primary tauopathies we see in these sporadic diseases like corticobasal degeneration and PSP, there seems to be far too much four repeat tau, and in a different tauopathy called Pick's disease, which causes frontotemporal dementia, there's too much three repeat tau. So it seems that having too much or an imbalance of isoforms may be toxic to neurons.
It turns out also that there are rare families around the world who have autosomal dominant mutations in the tau gene itself, and these give rise to severe early-onset forms of dementia or movement disorders. Remarkably, where the mutation is in the tau gene has a big effect on how the mutation exerts its effect biologically, and also on the phenotype or the symptoms produced by that mutation. For example, mutations in intron 10 lead to too much production of four-repeat tau and the individuals who have those mutations often develop clinical symptoms that look like CBD or PSP.
Conversely, when we do a genome-wide association study of the sporadic, the non-genetically determined diseases, CBD and PSP, we find the strongest genetic risk factor are single-nucleotide polymorphisms or sequences in or around the tau gene itself, with one particular sequence called H1C probably increasing the amount of tau expression and greatly increasing risk for these diseases. We now know that there are other genes that have been identified that may help to reduce the amount of tau expression or improve its clearance by the cells that are protective against these diseases. Why am I mentioning this?
Well, it is important as we think about the possible indications for tau-targeted drugs, that in those who have studied the drug development in general, the odds of bringing a drug successfully to market is much higher if there is a strong genetic link between the target of the drug and the disease itself. What I have mentioned is that with tau, there are very strong links to primary tauopathies, but less though for Alzheimer's disease. In fact, most of the mouse models that have been used to develop tau-targeting drugs are made with these mutations, P301L and P301S, that cause human early-onset frontotemporal dementia. We have already seen promising clinical data from diranersen in patients with Alzheimer's disease. What I want to make the case for is that there may be even a stronger rationale from a genetic perspective to treat.
What is going on with Alzheimer's disease if there is no genetic link? Why do we think that we should be treating these patients with the tau therapy? Well, you already saw the relationship temporally and neuropathologically between tau and Alzheimer's disease. A recent study from Judith Steen at Boston Children's that we helped with showed that although genetically, there is not much of a link between tau and Alzheimer's disease. At autopsy, when you quantify the amount of insoluble tau in that right-most column in the brain when someone passes away, there is about 50-fold higher levels of insoluble tau, that brown stuff I showed you in the first slide, than there is in the primary tauopathies or in controls. Alzheimer's disease is really a disease of too much tau, but it may be building up for other reasons. What have we said?
Well, we think that the central hypothesis of Alzheimer's disease is that tau is really leading to the clinical symptoms of disease. This is promoted by having amyloid plaques in the brain for decades. There was a worry, and before we talk about the phase II results with diranersen, that most of these hypotheses were based on observational or correlative data, and maybe the tau that we measure in living humans or people who come to autopsy is just a marker of some other pathogenic process. The alternative hypothesis is that tau increases with these diseases, but something else is really leading to the clinical symptoms. That is why the phase II diranersen trial was so important for the field. Again, I told you that in PSP, in primary tauopathies, we think that really tau is the only pathogenic protein that is present in most cases.
We have much greater confidence based on that and the genetic link that it is the tau that is the real problem. Of course, in tau mutation carriers, we know 100% for certain that it is the tau that is causing the disease. Many have seen these results. These are from the Biogen diranersen trial. Remarkably for the field, what was shown is that reducing tau by 60%, roughly, in the CSF in patients with prodromal to mild Alzheimer's disease, was also associated with a 40% or 42% slowing of cognitive decline at the optimal dose, which turned out to be the lowest and not the highest dose of drug.
This is really remarkable because it helps to support this hypothesis that tau is a central pathogenic protein in Alzheimer's disease because all of these patients still had high levels of amyloid in their brain, but reducing tau was associated with a clinical benefit. Unfortunately, this trial did not produce the results we had all hoped for, which was across-the-board benefits. There was less of an effect seen on activities of daily living or on global measures like the Clinical Dementia Rating scale that I showed you in the slide with donanemab early. The question is: why wasn't there a bigger clinical effect of reduction of tau? Why was it only 42%? Why was it only at the lowest dose?
Well, one thing that was reported in these results at AAIC was that there were dose-related side effects, either confusion and falls, most commonly in the one week following injection. Maybe these mitigated some of the benefits of lowering tau in these patients. You can see in the lower right-hand corner, in the subset of people who received longitudinal tau PET, that in orange, this was the optimal dose, and this had the least amount of insoluble tau reduction, but there was insoluble tau reduction. One question that we are all struggling with in the field right now is, was there something about diranersen because it is an intrathecally administered ASO that is leading to these side effects that cause confusion and falls, and maybe it is inflammation, maybe this was mitigating the benefit of reducing tau.
Alternatively, and we hope this is not the case, but we don't know for sure, maybe there was some on-target toxicity of tau reduction. Even though reducing tau in animals has been benign, and genetic studies of humans suggest that loss of tau function is not associated with disease, maybe what this study is telling us is that maybe there is a limit to what we can do. I think we just can't resolve these based on these data. Other possible reasons why more prominent clinical benefits were not observed in the study. Well, maybe they started too late in disease. Maybe you have to start earlier in the catastrophe. Maybe you need to remove both A-beta, I mentioned that the A-beta was still present in these patients, and tau, and also maybe in the future, other pathogenic proteins like alpha-synuclein.
About 30% of these individuals were also found to be alpha-synuclein positive. In another study funded by the U.S. National Institutes of Health, we are doing a platform trial where we are combining amyloid and tau therapies. I am not here to tell you about that, but combination therapy may be something that we will do in the future to really see the greatest benefits. Of course, as I suggested to you earlier, maybe primary tauopathies will respond better. This is an important insight that we have had from new technology called cryo-electron microscopy. Really, it turns out that using this technology, we have been able to solve the three-dimensional structure of the aggregates and the various primary and secondary tauopathies.
What we have learned is that it is that the core structure, which corresponds with the microtubule binding domain, has a very regular, what we call amyloid structure in each of the tauopathies, and that in different tauopathies, remarkably, the three-dimensional structure of this core is different. Maybe it is actually the core that is driving the disease or the actual structure of these aggregates. We do not know for sure, but what we do know is that there are many other therapeutic approaches to tau. Many of them are immunotherapies, and the first five or so failed. We think that the reason why they failed is because instead of targeting the tau core structure, they targeted the N-terminal regions of tau, which I told you earlier, are often cleaved off. Some of the newer immunotherapies target this core structure and are beginning to produce more promising results.
There may be other approaches to tau therapies, particularly immunotherapies that target this toxic core structure that might also eventually find their way to the clinic. One example, or the first example that has been tested in a large phase II was bepranemab, and in a post-hoc study, in individuals who either had low tau at baseline or APOE4 non-carriers in the upper left-hand panel, or excuse me, the middle left-hand panel, you can see that this antibody that reduced extracellular tau by binding to the N-terminal portion of the microtubule binding region, seemed to attenuate tau PET uptake and also slow cognitive decline on the ADAS-Cog.
Again, these data were presented a few years ago, but this was very important for the field because it was the first experimental demonstration with an interventional study in living humans that neutralizing extracellular tau with a monoclonal antibody had a clinical benefit or potential clinical benefit. This really supported the hypothesis that tau spreads from one cell to another through the extracellular space. These are, I think, promising developments for tau therapeutics. What about primary tauopathies? Remarkably, we have been doing clinical trials in progressive supranuclear palsy for over 20 years. But for the first time, earlier this year, presented at ADPD, a trial with a different antisense oligonucleotide called NIO752, showed that in patients with PSP Richardson syndrome, reduction of tau in the CSF by about 25%-30% was associated with a stabilization of neurodegeneration as measured by CSF neurofilament levels.
Neurofilament is an axonal protein that is released when neurons degenerate. This was really remarkable because never before in a clinical trial in PSP had we ever seen anything that seemed to have an effect on neurodegeneration or disease modification. This drug is now in a phase III study. To summarize, what I have told you is that targeting tau really reflects the close clinical pathological correlation between insoluble tau accumulation and many different neurodegenerative diseases of aging, not just Alzheimer's disease. Reducing production and targeting all forms of tau may be a pragmatic solution. You have seen the challenges with immunotherapies. There are exciting results with both diranersen and NIO752, two other genetically targeted tau therapies, and we are eagerly awaiting the next round of results with these drugs.
There is a huge global unmet need for both Alzheimer's disease, but for primary tauopathies in particular, because these are severe diseases with no approved therapies that can help these patients. We think, or I think, that there is a very strong rationale for testing tau therapies outside of Alzheimer's disease. I told you that there are very strong genetic links suggesting maybe even these drugs might even potentially work better for primary tauopathies. With that, I am going to end, and I am sure there will be time for questions, and I will turn this over to James. Thank you.
Thank you, Adam, for that great overview. Now we will switch gears and talk about our platform and the ARO-MAPT study. For those of you who are new to the story, Arrowhead remains focused exclusively on developing siRNA therapeutics. We leverage the TRiM platform, which is a set of rules and algorithms for sequence selection, coupled with a library of linkers and targeting ligands to facilitate siRNA delivery into multiple cell types. Any given platform is modular, which allows for a degree of repeatability in GLP toxicology studies and drug manufacturing. Broadly, the TRiM discovery platform is designed to facilitate rapid progression from concept to clinic. The CNS platform uses a TFR1-targeted Fab covalently linked to the siRNA payload to facilitate subcutaneous administration and effective delivery of siRNA across the blood-brain barrier.
This strategy has several advantages over the intrathecal route of administration, which will be described in the next few slides. Here in monkey studies, we have confirmed the ability of the platform to silence MAPT expression by better than 75% across various brain regions with subcutaneous administration of development candidate ARO-MAPT. This includes effective silencing in Alzheimer's disease-relevant brain regions, including the hippocampus. In a long-term multi-dose monkey study, we confirmed the ability to maintain MAPT silencing after repeated doses. These data support long duration of effect with up to 60% CSF tau knockdown up to four months after the last dose. Importantly, the knockdown achieved with subcutaneous administration of siRNA delivered across the blood-brain barrier using the Arrowhead CNS platform is more consistent and more homogeneous, as shown on the right, compared with intrathecal delivery of siRNA targeting MAPT, as shown on the left.
This is important because better distribution avoids concentration of drug in the spinal cord, as is common with IT delivery, and facilitates potentially better gene target silencing in the most relevant brain regions. Here again, we emphasize the more homogeneous drug concentrations achieved across various disease-relevant brain regions with subcutaneous administration using the Arrowhead platform, as shown in monkeys on the left. This is compared to the highly heterogeneous delivery seen with IT administration and IT-administered ASO in a clinical radiotracer study, as shown on the right. Note the lack of signal in the brain in some participants in the panel on the right and the strong signal seen in the lumbar spinal cord. Now that we've reviewed the platform, let's switch to the ARO-MAPT clinical study. ARO-MAPT-SC-1001 is a dose-escalating study of ARO-MAPT in healthy volunteers and in patients with early Alzheimer's.
The study is intended to understand safety, PK, and pharmacodynamic response in healthy volunteers and in Alzheimer's patients using multiple escalating dose levels and various dose interval strategies. The Alzheimer's patient cohorts will enroll individuals 50 - 80 years of age with early Alzheimer's based on CDR and MMSE score cutoffs, as well as the presence of at least one biomarker consistent with Alzheimer's. Participants must not be on or have no plans to initiate Alzheimer's disease-modifying therapies, including anti-amyloid therapy, for the duration of the study. The study has or will have sites open in Canada, U.K., Australia, and New Zealand, and the healthy volunteer enrollment is complete. We're currently focused on enrolling the Alzheimer's patient cohorts.
Primary endpoint of the study is safety, but we have multiple pharmacodynamic endpoints built into both the healthy volunteer and the Alzheimer's disease patient components of the study, and we will be evaluating various cognitive rating scales in patients. However, today we'll be focusing on the data that's available from the healthy volunteer single escalating dose cohorts. Briefly here, we show baseline characteristics generally consistent with those of a typical healthy volunteer population. Here we show CSF total tau reduction over time by dose group. After the initial loading dose, we're seeing mean CSF tau reductions of up to 73% and a maximal individual reduction of up to 85%, with evidence of dose response and with no reductions in the placebo group.
On the next slide, we show individual CSF tau responses indicating a generally consistent post-dose magnitude of tau reduction across individuals receiving ARO-MAPT, compared with no response in placebo. Available safety data so far are supportive of continued dose administration and of progression to later-stage studies. ARO-MAPT has been well-tolerated, with no reported serious treatment emergent AEs, no neurobehavioral AEs such as confusion, and no persistent anemia. In terms of next steps, we plan to first finish dosing in the multiple ascending dose cohorts in healthy volunteers with a planned data update next year. We also plan to continue enrollment in the Alzheimer's patient cohorts, also with a planned data update in 2027. We have initiated discussions with regulators in anticipation of later-stage studies in MAPT variant frontotemporal dementia and progressive supranuclear palsy.
In conclusion, Arrowhead's subcutaneous CNS siRNA delivery platform has been well-tolerated to date in healthy volunteers and Alzheimer's patients. Subcutaneous administration of ARO-MAPT in healthy volunteers has demonstrated deep dose-dependent and durable knockdown of CSF total tau, with potential for more homogeneous brain distribution. These data represent initial clinical validation of ARO-MAPT and, importantly, of the TRiM CNS platform, which is an important milestone for Arrowhead and also for our partners using this platform. In addition to ARO-MAPT, Arrowhead has multiple wholly-owned CNS-targeted preclinical development programs, including two planned for CTAs by end of 2026 or early 2027. I'll now hand the call back over to our President and CEO, Chris Anzalone. Chris?
Thanks, James. Next slide. We believe that what we have shown today represents scientific and potential therapeutic breakthroughs, and this is just the first step. It appears that we are able to deliver siRNA to the CNS across the blood-brain barrier in a well-tolerated manner. Administration is by simple subcutaneous injection that could potentially be done at home, as infrequently as quarterly. We see deep and durable knockdown that we expect is occurring across brain regions, including the deep brain. We could see even deeper and more durable knockdown after multiple doses. Our non-clinical work in the CNS and extensive clinical and non-clinical work in other cell types have suggested that once we validate our ability to deliver to a particular cell type, we can reliably reproduce that against other targets.
Simply put, it appears that cells don't care what siRNA sequence we use, so this early clinical proof of concept could have wide-ranging predictive value across any number of disease treatments. With a minimally invasive platform that enables us to silence virtually any gene expression in the brain, including in both neurons and neuroglia, we should be able to address conditions from neurodegenerative, to psychiatric, to sleep disorders, to migraines, to obesity, and others. It is difficult to overstate the flexibility and importance of this platform. We believe we are limited only by the number of targets we can identify. But let's also focus on the leap forward we see in the current candidate, ARO-MAPT. The biology around primary tauopathies is fairly clear, and ARO-MAPT could be a powerful therapy for many of these patients.
The regulatory pathway could also be fairly straightforward and relatively short, so we hope to bring ARO-MAPT to these patients as quickly as possible. More broadly, we hope to bring ARO-MAPT to the approximately 30 million - 40 million people worldwide suffering from Alzheimer's disease. Of course, this is a longer regulatory road and there is more biology to learn, but we look forward to our first data in patients with Alzheimer's next year. Next slide. We now have clinical proof of concept for the TRiM platform's ability to deliver to five different organ systems. As I mentioned earlier in the presentation today, our model is to bring RNAi to wherever disease is, and the current expansion into CNS substantially increases our reach. We continue to build the platform and expect to reach a new cell type every 18 - 24 months. Next slide.
In 2026 alone, Arrowhead has further solidified its position as the leading innovator in RNAi therapeutics. In less than a year, we believe we are the first to achieve clinical proof of concept of RNAi in the brain after subcutaneous administration, achieve clinical proof of concept of silencing two genes with a single molecule
And achieve clinical proof of concept of RNAi targeted in adipocytes. We tend to continue this pace in 2027 and beyond. With respect to follow-up on these achievements, we expect to present additional data in healthy volunteers and Alzheimer's patients with ARO-MAPT in 2027 and introduce at least four additional CNS candidates into the clinic by the end of 2027. To present additional clinical data with ARO-DIMER-PA in 2027 and introduce at least one new dimer to the clinic next year, and to present additional clinical data for ARO-ALK7 by the end of 2026. With that, I'd now like to open the call to your questions, and thank you for your attention today.
Thanks, everybody. Let me compile some questions. We have time for three or four separate questions. Okay. First question is from Madison El-Saadi at B. Riley. Looks like the first part of this will be for Dr. Boxer, and then the second part probably for James. First part is, could the planned FTD and PSP studies reach approval faster than Alzheimer's, and what would a design look like for those types of clinical studies? So we'll start there—
Yeah
—and then I'll get the second part after.
That's a great question. I'm not a regulatory expert, but my understanding is that these are both rare diseases, or they're considered orphan diseases with severe unmet need. There are no approved therapies. In the United States at least, there are mechanisms, regulatory mechanisms to encourage the development. I think there may also be some patent exclusivity benefits as well, that may allow a more rapid development and certain additional considerations for approvals. Also because these are rare disease populations, often it's not possible to do multiple different stages of development. Often it's a phase I and then a large phase II/III. We do think there are significant advantages. The third reason is that these diseases tend to have a much more rapid rate of progression, so you can do a faster, smaller, more efficient trial.
Just one last plug, which is the National Institutes of Health are also supporting a platform trial for progressive supranuclear palsy, which is up and enrolling now. We hope that drugs like this could find their way into our platform trial.
Great, thanks. James, what's the timeline for additional regulatory interactions, and when would we assume that we'll start FTD and PSP studies?
Yeah, so we're having those discussions now. I think over the next one to two quarters should have quite a bit of meaningful back and forth on the regulatory front with an aim of finalizing a study design. Probably don't want to give guidance on timing to start those studies until we at least have the study design pinned down, but we'd be aiming to start something in 2027.
Great, thanks. Next question is from Jason Gerberry at Bank of America, and I would also think this is probably Dr. Boxer. Which downstream measures would you expect to change if MAPT silencing is disease modifying? For example, tau PET, neurofilament light, MRI measures, synaptic measures, neuroinflammation markers, or another endpoint, and over what observation period could these changes reasonably become detectable? I would split in two, Alzheimer's as well as primary tauopathies.
Answering that question, but as I mentioned, in Alzheimer's disease, we have the advantage that we can measure tau PET and soluble forms of tau pretty easily, even in blood. That would be the first thing that we'd look at. Then again, there are well-established clinical and other biomarker endpoints in Alzheimer's disease. For primary tauopathies, unfortunately, we don't have as good biomarkers of tau. We can measure for target engagement, CSF tau levels and p-tau levels. We don't yet have as good tau PET ligands. But as I already showed you, neurofilament light chain, because these are more aggressive diseases, tends to be more elevated in primary tauopathies, in PSP and tau mutation carriers. Also, MRI may be a good endpoint.
Increasingly now, coming out of proteomic studies, there's very clear evidence that there are other fluid biomarkers, like biomarkers of synaptic connectivity, one's called the synaptic protein ratio, that may be particularly sensitive to these effects. We would hope, again, these are, unfortunately for the patients, more aggressive diseases. So for PSP, a typical study is one year. Depending on when we would start, what stage of disease, a MAPT mutation carrier trial might be a little longer, 18 months to two years.
Thank you. Next question comes from Prakhar Agrawal at Cantor. What is the timing of Alzheimer's disease patient data? Actually, I'll head that off before James even gets to that. So in 2027, at some point. We have to see how those studies start enrolling. The next part of this question will probably be James and Dr. Boxer. Based on the knockdown data that you're seeing in healthy volunteers, what level of knockdown would you expect in patients, and how are you thinking about the optimal dose here? Seems like an intermediate dose of 6.4 mg per kilogram and 12.8 mg per kilogram showed mostly comparable data.
Yeah. I can start on that one. I agree. I think that at least after that loading dose, either day one, eight, 15 or day one, 15, that with those top few dose regimens, either 6.4 mg per kilogram or the 12.8 mg per kilogram, they look very similar, right? So we may be hitting the top of the dose response curve. In that case, if they all look similar, we'd probably select the lower end of that dosing range if there's no benefit to going higher. That being said, we'll have to see how things evolve after we give the next dose, and we'll also have to see how things look in the patients. Dr. Boxer can comment on this, but the kinetics of tau might be different in Alzheimer's patients.
And so we'll see how knockdown looks at the various dose levels and different dosing strategies in patients compared to what we saw in healthy volunteers. We just don't know yet.
Yeah. I would agree with James that it's exciting to see these initial results, but there's still a lot more to learn. As I showed you earlier, the slide from Judith Steen, there's a huge amount of tau in Alzheimer's disease. We don't quite understand why there's so much of it, but the kinetics might be different. So, there's a lot more to understand, and we're excited to learn more from this compound.
Thank you. Next question is James Condulis at Stifel. "One thing we've seen in the BIIB080 clinical data is that the tau PET benefit was lower than CSF tau. Do you think that's a function of its IT dosing and potentially reflective of insufficient knockdown in the brain? In that context, can you talk about confidence that this CSF data is reflective of broad biodistribution throughout the brain?
I think it's a great question. I think it's important to consider the chemistry. I know we're not all chemists here, but when you measure the CSF levels of tau, you're looking at that N-terminal portion of tau that's soluble, that's floating around in the liquid phase. When we measure PET, we're looking at the insoluble aggregated clumps of protein. They're solid. These two phases of tau, these two different forms of tau, are in equilibrium. The important thing that we learned from diranersen in the phase I is that we thought that there was a one directional arrow going from the soluble phase to the insoluble phase. Once there were these insoluble aggregates, they never could go away. That turns out not to be true.
What does probably seem to be the case, and it's just common chemistry, is that it's really easy for something to go from the soluble phase to the insoluble phase, but much slower in the opposite direction. To answer your question, these CSF biomarkers, I think, are much likely to be very much more responsive to the actual near term pharmacodynamic effects of tau knockdown. I do think that they accurately reflect the effects on tau protein. But there's going to be a very long lag. In what you're measuring with tau PET, just due to the chemistry and due to the physical chemistry of trying to go from the solid phase back into the liquid phase.
Thank you. Next question is from Mayank Mamtani at B. Riley Securities. Second part of his question is, "How does the subQ route change feasibility versus intrathecal in these? That probably applies to both clinical trial recruitment as well as in clinical practice, if these get approved.
Yeah. I think, well, I'll answer first and then James might. I think it's super exciting. Many of us are less willing to get a lumbar puncture. It's not really a big deal, but it's still more invasive than a subcutaneous injection, and that is a barrier to enrollment in clinical trials and sometimes a barrier to, even after a drug is approved, to someone agreeing to receive it. It can be more work for physicians to administer or for clinical staff to administer an intrathecal drug. Obviously, you can't do that in the convenience of your own home. For the rare tauopathies, and particularly when we talk about tau mutation carriers, this is extremely exciting because many of them are distributed in countries around the world where the healthcare system isn't as well developed as in the United States.
It may be really hard to get these therapies to people who really need them and administer them if it's by an intrathecal route. One could really envision that a subcutaneously administered drug could really find its way around the world in a clinical trial and really, really offer great hope to these people if it works.
You.
Yeah. I echo that from just a clinical trial execution standpoint. We're still doing lumbar punctures to measure CSF, various CSF biomarkers in the phase I. Maybe in some of the phase IIs we'll do it. We don't have to administer drug through that route. I think that allows you to maybe reduce the number of lumbar punctures that are going to occur in clinical trials. Maybe by phase III, you could totally eliminate them from clinical trials. There's also probably just a different toxicity profile of administering drug directly into the intrathecal space compared to what you see with a subQ route.
Thank you. I think we have time for just one last question. Since ARO-MAPT reduces both pathogenic and healthy isoforms of tau, where tau also has physiologic function, can you frame how you're thinking about a therapeutic window for tau reduction? I would maybe ask Dr. Boxer that first, and then James can chime in there. Is there a sweet spot there for reducing it enough but not too much?
Yeah, I think that's the key question for our field right now, honestly. Again, in animals, you can knock down tau to zero, and it seems to be pretty safe and well-tolerated. If you look at large human genetic studies looking for tau associated genetic in tau that's associated with human disease is gain of function, so there's too much tau or misfolding, never loss of function. So there's never been a case that we know of tau loss of function associated with disease. But the diranersen results are producing questions. There's just a lot more that we need to understand, and we need to probably look at these different drugs and different doses and different populations before we can answer this question.
Yeah, I would agree. I think what we have right now are safety data with relatively short-term tau knockdown in healthy volunteers. If you maintain that knockdown, we haven't seen any associated safety issues with that knockdown, but again, it hasn't been over years and years. At least short term, it seems relatively safe. But we need to select the right dose level and the right level of tau reduction. I think it's going to depend a lot more on what we see in these patient cohorts in terms of changes in the other biomarkers, things like NfL, things like PET in Alzheimer's patients, but also in the primary tauopathy patients.
Thank you. Actually, we have one more question. We have about a minute left, so a quick one for Dr. Boxer. This is from Eric Joseph at Citi, and he wants to know what you would view as a clinically meaningful slowing of dementia progression in AD patients over one to two years.
I would say similar to what's already been seen with the anti-amyloid drugs. I think it's clinically meaningful for our patients who are being treated already. If we see something comparable with tau drugs, I think that's really encouraging. Again, the future may be combination therapy, and when we combine anti-amyloid and anti-tau, there's a potential for a synergistic effect. I think the future is really exciting for our patients and for all of us who are getting older.
Thank you. Thank you, Dr. Boxer, and James and Chris as well, and thanks everybody for joining us today.
Thanks, everyone.